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Cholesterol modulates ion channels via down‐regulation of phosphatidylinositol 4,5‐bisphosphate
Author(s) -
Chun Yoon Sun,
Shin Sora,
Kim Yonjung,
Cho Hana,
Park Myoung Kyu,
Kim TaeWan,
Voronov Sergey V.,
Di Paolo Gilbert,
Suh ByungChang,
Chung Sungkwon
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06545.x
Subject(s) - cholesterol , herg , phosphatidylinositol 4,5 bisphosphate , chemistry , phosphatidylinositol , ion channel , phospholipase c , biochemistry , patch clamp , potassium channel , biophysics , biology , signal transduction , receptor
J. Neurochem. (2010) 112 , 1286–1294. Abstract Ubiquitously expressed Mg 2+ ‐inhibitory cation (MIC) channels are permeable to Ca 2+ and Mg 2+ and are essential for cell viability. When membrane cholesterol level was increased by pre‐incubating cells with a water‐soluble form of cholesterol, the endogenous MIC current in HEK293 cells was negatively regulated. The application of phosphatidylinositol 4,5‐bisphosphate (PIP 2 ) recovered MIC current from cholesterol effect. As PIP 2 is the direct modulator for MIC channels, high cholesterol content may cause down‐regulation of PIP 2 . To test this possibility, we examined the effect of cholesterol on two exogenously expressed PIP 2 ‐sensitive K + channels: human Ether‐a‐go‐go related gene (HERG) and KCNQ. Enrichment with cholesterol inhibited HERG currents, while inclusion of PIP 2 in the pipette solution blocked the cholesterol effect. KCNQ channel was also inhibited by cholesterol. The effects of cholesterol on these channels were blocked by pre‐incubating cells with inhibitors for phospholipase C, which may indicate that cholesterol enrichment induces the depletion of PIP 2 via phospholipase C activation. Lipid analysis showed that cholesterol enrichment reduced γ‐ 32 P incorporation into PIP 2 by approximately 35%. Our results suggest that cholesterol may modulate ion channels by changing the levels of PIP 2 . Thus, an important cross‐talk exists among two plasma membrane‐enriched lipids, cholesterol and PIP 2 .